Endogenous Damage-associated Molecular Patterns Research Articles

Systemic levels of the anti-inflammatory decoy receptor soluble RAGE (receptor for advanced glycation end products) are decreased in dogs with inflammatory bowel disease

Inflammatory bowel disease (IBD) is a common condition in dogs, and a dysregulated innate immunity is believed to play a major role in its pathogenesis. S100A12 is an endogenous damage-associated molecular pattern molecule, which is involved in phagocyte activation and is increased in serum/fecal samples from dogs with IBD. S100A12 binds to the receptor of advanced glycation end products (RAGE), a pattern-recognition receptor, and results of studies in human patients with IBD and other conditions suggest a role of RAGE in chronic inflammation. Soluble RAGE (sRAGE), a decoy receptor for inflammatory proteins (e.g., S100A12) that appears to function as an anti-inflammatory molecule, was shown to be decreased in human IBD patients. This study aimed to evaluate serum sRAGE and serum/fecal S100A12 concentrations in dogs with IBD.Serum and fecal samples were collected from 20 dogs with IBD before and after initiation of medical treatment and from 15 healthy control dogs. Serum sRAGE and serum and fecal S100A12 concentrations were measured by ELISA, and were compared between dogs with IBD and healthy controls, and between dogs with a positive outcome (i.e., clinical remission, n=13) and those that were euthanized (n=6). The relationship of serum sRAGE concentrations with clinical disease activity (using the CIBDAI scoring system), serum and fecal S100A12 concentrations, and histologic disease severity (using a 4-point semi-quantitative grading system) was tested.Serum sRAGE concentrations were significantly lower in dogs with IBD than in healthy controls (p=0.0003), but were not correlated with the severity of histologic lesions (p=0.4241), the CIBDAI score before (p=0.0967) or after treatment (p=0.1067), the serum S100A12 concentration before (p=0.9214) and after treatment (p=0.4411), or with the individual outcome (p=0.4066). Clinical remission and the change in serum sRAGE concentration after treatment were not significantly associated (p=0.5727); however, serum sRAGE concentrations increased only in IBD dogs with complete clinical remission. Also, dogs that were euthanized had significantly higher fecal S100A12 concentrations than dogs that were alive at the end of the study (p=0.0124).This study showed that serum sRAGE concentrations are decreased in dogs diagnosed with IBD compared to healthy dogs, suggesting that sRAGE/RAGE may be involved in the pathogenesis of canine IBD. Lack of correlation between sRAGE and S100A12 concentrations is consistent with sRAGE functioning as a non-specific decoy receptor. Further studies need to evaluate the gastrointestinal mucosal expression of RAGE in healthy and diseased dogs, and also the formation of S100A12-RAGE complexes.

Toll-like receptor-4 modulation for cancer immunotherapy.

Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition molecules. Since the discovery of the Toll pathway cascade (1, 2), our knowledge about the structure, function, and mechanics of TLRs in infectious and inflammatory conditions has increased remarkably. The role of TLR4 as a pathogen-pattern recognition receptor has been studied extensively. We now know that TLR4 recognizes pathogen-associated molecular patterns (PAMPs), such as Gram-negative bacterial lipopolysaccharide (LPS) and endogenous damage-associated molecular patterns (DAMPs) like fibronectin and hyaluronan, which are released during infectious and non-infectious inflammatory conditions. Some chronic infections and inflammatory conditions are known to promote carcinogenesis. For example, Helicobacter pylori (3) and viral hepatitis (4) infections lead to gastric and liver cancers, respectively. Also, in inflammatory bowel disease, non-infectious inflammation promotes the development of colorectal cancer (5). Evidence from recent reports suggests that increased expression and activity of TLR4 in chronic infectious and inflammatory conditions is associated with cancer progression (6–8). At the same time, additional studies suggest the protective role of TLR4 in cancer (9–14). The role of TLR4 in cancer has only recently been studied. This review article provides a brief summary of the current understanding of TLR4-signaling, its pro- and anti-cancer effects, and the therapeutic potential of TLR4 immunomodulation in the prevention and treatment of cancer.

Innate signaling in the inflammatory immune disorders

Pattern recognition receptors (PRRs) of innate immune cells recognize the conserved molecular signatures on pathogens, termed pathogen-associated molecular patterns. PRRs also recognize endogenous damage-associated molecular patterns. Following pathogen infection or tissue damage, the stimulation of PRRs activates distinct but shared signaling pathways that lead to effector mechanisms in innate host defense. PRR signaling is strictly and finely tuned to ensure the appropriate duration and strength to prevent damaging inflammation to the host. Here we attempt to provide a brief background on the agonists and signal transduction pathways of PRRs and summarize the mechanisms underlying the control of PRR signaling, with a particular focus on the recent progress of the involvement of PRR signaling in the inflammatory immune disorders.

Toll-like receptors and hypertension.

Hypertension and associated inflammatory processes that accelerate cardiovascular damage are regulated by the innate immune system. Toll-like receptors (TLR) are major components of the innate immune system that recognize endogenous damage-associated molecular patterns to activate prominent inflammatory signaling including activation of nuclear factor-κB (NF-κB). However, the role of TLR in the etiology of hypertension is not well understood. TLR signaling is dependent on adaptor proteins that, along with the TLR expression patterns, confer specificity of the inflammatory response and its pathological targets. Here we review the conceptual framework of how TLR and their adaptor proteins may differentially affect hypertension and cardiac hypertrophy by different stimuli.

Functional Characterization of S100A8 and S100A9 in Altering Monolayer Permeability of Human Umbilical Endothelial Cells

S100A8, S100A9 and S100A8/A9 complexes have been known as important endogenous damage-associated molecular pattern (DAMP) proteins. But the pathophysiological roles of S100A8, S100A9 and S100A8/A9 in cardiovascular diseases are incompletely explained. In this present study, the effects of homo S100A8, S100A9 and their hetero-complex S100A8/A9 on endothelial barrier function were tested respectively in cultured human umbilical venous endothelial cells (HUVECs). The involvement of TLR4 and RAGE were observed by using inhibitor of TLR4 and blocking antibody of RAGE. The clarification of different MAPK subtypes in S100A8/A9-induced endothelial response was implemented by using specific inhibitors. The calcium-dependency was detected in the absence of Ca2+ or in the presence of gradient-dose Ca2+. The results showed that S100A8, S100A9 and S100A8/A9 could induce F-actin and ZO-1 disorganization in HUVECs and evoked the increases of HUVEC monolayer permeability in a dose- and time-dependent manner. The effects of S100A8, S100A9 and S100A8/A9 on endothelial barrier function depended on the activation of p38 and ERK1/2 signal pathways through receptors TLR4 and RAGE. Most importantly, we revealed the preference of S100A8 on TLR4 and S100A9 on RAGE in HUVECs. The results also showed the calcium dependency in S100A8- and S100A9-evoked endothelial response, indicating that calcium dependency on formation of S100A8 or A9 dimmers might be the prerequisite for this endothelial functional alteration.

Role of Toll-like receptor-4 in renal graft ischemia-reperfusion injury

Toll-like receptor-4 (TLR-4) has been increasingly recognized as playing a critical role in the pathogenesis of ischemia-reperfusion injury (IRI) of renal grafts. This review provides a detailed overview of the new understanding of the involvement of TLR-4 in ischemia-reperfusion injury of renal grafts and its clinical significance in renal transplantation. TLR-4 not only responds to exogenous microbial motifs but can also recognize molecules which are released by stressed and necrotic cells, as well as degraded products of endogenous macromolecules. Upregulation of TLR-4 is found in tubular epithelial cells, vascular endothelial cells, and infiltrating leukocytes during renal ischemia-reperfusion injury, which is induced by massive release of endogenous damage-associated molecular pattern molecules such as high-mobility group box chromosomal protein 1. Activation of TLR-4 promotes the release of proinflammatory mediators, facilitates leukocyte migration and infiltration, activates the innate and adaptive immune system, and potentiates renal fibrosis. TLR-4 inhibition serves as the target of pharmacological agents, which could attenuate ischemia-reperfusion injury and associated delayed graft function and allograft rejection. There is evidence in the literature showing that targeting TLR-4 could improve long-term transplantation outcomes. Given the pivotal role of TLR-4 in ischemia-reperfusion injury and associated delayed graft function and allograft rejection, inhibition of TLR-4 using pharmacological agents could be beneficial for long-term graft survival.

Antimicrobial Cathelicidin Peptide LL-37 Inhibits the LPS/ATP-Induced Pyroptosis of Macrophages by Dual Mechanism

Pyroptosis is a caspase-1 dependent cell death, associated with proinflammatory cytokine production, and is considered to play a crucial role in sepsis. Pyroptosis is induced by the two distinct stimuli, microbial PAMPs (pathogen associated molecular patterns) and endogenous DAMPs (damage associated molecular patterns). Importantly, cathelicidin-related AMPs (antimicrobial peptides) have a role in innate immune defense. Notably, human cathelicidin LL-37 exhibits the protective effect on the septic animal models. Thus, in this study, to elucidate the mechanism for the protective action of LL-37 on sepsis, we utilized LPS (lipopolysaccharide) and ATP (adenosine triphosphate) as a PAMP and a DAMP, respectively, and examined the effect of LL-37 on the LPS/ATP-induced pyroptosis of macrophage-like J774 cells. The data indicated that the stimulation of J774 cells with LPS and ATP induces the features of pyroptosis, including the expression of IL-1β mRNA and protein, activation of caspase-1, inflammasome formation and cell death. Moreover, LL-37 inhibits the LPS/ATP-induced IL-1β expression, caspase-1 activation, inflammasome formation, as well as cell death. Notably, LL-37 suppressed the LPS binding to target cells and ATP-induced/P2X7-mediated caspase-1 activation. Together these observations suggest that LL-37 potently inhibits the LPS/ATP-induced pyroptosis by both neutralizing the action of LPS and inhibiting the response of P2X7 to ATP. Thus, the present finding may provide a novel insight into the modulation of sepsis utilizing LL-37 with a dual action on the LPS binding and P2X7 activation.

Abstract 189: Toll-like Receptor 2 Blockade Decreases Contractility in Angiotensin II-induced Hypertensive Rat Resistance Arteries

Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system that recognize endogenous damage-associated molecular patterns (DAMPS). TLR2 plays a role in cardiovascular diseases such as atherosclerosis and heart failure, but its role in hypertension is unknown. Angiotensin II (ANG), the effector molecule of the renin-angiotensin system, has been shown to cause an immune response leading to an inflammatory profile, in addition to its effects on vascular tone and sodium balance. We hypothesized that signaling through TLR2 in ANG-induced hypertension contributes to an increase in resistance artery contractility and vascular dysfunction. Sprague-Dawley rats were implanted with osmotic mini-pumps dispensing ANG (60 mg/day) for a 28 day period. Systolic blood pressure (measured directly via femoral canulation to confirm the ANG rats as a model of hypertension) was significantly increased in the ANG-treated rats (170 ±4.79 mmHg) vs. control (97 ±6.9 mmHg (p<0.05)). Concentration response curves to norepinephrine (NE; 10-9-10-4 M) were performed in second and third order mesenteric arteries from control and angiotensin-treated rats. Vessels were pre-incubated with and without antibody to TLR2 (1μg) for 35 minutes prior to the concentration-response curves to determine the impact of TLR2 blockade. The EMax (force of contraction as % of maximum KCl response) of the ANG vessels treated with anti-TLR2 was significantly lower than that of the ANG vessels alone (EMax: 129.2±10.69% vs 183.8±16.73%, respectively), and comparable to control-vessel levels (EMax in control vessels: 135.1±4.360%, p<0.05). Additionally, we sought to determine protein levels of TLR2 and downstream signaling protein MyD88 in the mesenteric arteries. In the arteries from the ANG treated animals, TLR2 expression was significantly increased 2.95±0.20 fold above control, and MyD88 expression was increased 1.35±0.06 fold above control (p<0.05). This suggests that TLR2 signaling leads to augmented contractility and is associated with the vascular dysfunction observed in hypertension.

Mitochondrial-derived N-formyl peptides: Novel links between trauma, vascular collapse and sepsis

Sepsis is a major cause of mortality and morbidity in trauma patients despite aggressive treatment. Traumatic injury may trigger infective or non-infective systemic inflammatory response syndrome (SIRS) and sepsis. Sepsis and SIRS are accompanied by an inability to regulate the inflammatory response but the cause of this perturbation is still unknown. The major pathophysiological characteristic of sepsis is the vascular collapse (i.e., loss of control of vascular tone); however, at the cellular level the final mediator of extreme vasodilatation has yet to be identified. After trauma, cellular injury releases endogenous damage-associated molecular patterns (DAMPs) that activate the innate immune system. Mitochondrial DAMPs express at least two molecular signatures, N-formyl peptides and mitochondrial DNA that act on formyl peptide receptors (FPRs) and Toll-like receptor 9, respectively. N-Formyl peptides are potent immunocyte activators and, once released in the circulation, they induce modulation of vascular tone by cellular mechanisms that are not completely understood. We have observed that N-formyl peptides from bacterial (FMLP) and mitochondrial (FMIT) sources induce FPR-mediated vasodilatation in resistance arteries. Accordingly, we propose that tissue and cellular trauma induces the release of N-formyl peptides from mitochondria triggering inflammation and vascular collapse via activation of FPR and contributing to the development of sepsis. The proposed hypothesis provides clinically significant information linking trauma, mitochondrial N-formyl peptides and inflammation to vascular collapse and sepsis. If our hypothesis is true, it may lead to new strategies in the management of sepsis that can help clinicians effectively manage non-infectious and infectious inflammatory responses.

CD163 and IgG Codefend against Cytotoxic Hemoglobin via Autocrine and Paracrine Mechanisms

Lysis of RBCs during numerous clinical settings such as severe hemolytic anemia, infection, tissue injury, or blood transfusion releases the endogenous damage-associated molecular pattern, hemoglobin (Hb), into the plasma. The redox-reactive Hb generates cytotoxic reactive oxygen species, disrupting the redox balance and impairing the immune-responsive blood cells. Therefore, it is crucial to understand how the immune system defends against the cytotoxic Hb. We identified a shortcut "capture and quench" mechanism of detoxification of Hb by the monocyte scavenger receptor CD163, independent of the well-known dominant antioxidant, haptoglobin. Our findings support a highly efficient two-pass mechanism of detoxification and clearance of Hb: 1) a direct suppression of Hb-pseudoperoxidase activity by CD163, involving an autocrine loop of CD163 shedding, sequestration of Hb, recycling, and homeostasis of CD163 in human monocytes and 2) paracrine transactivation of endothelial cells by the shedded soluble CD163 (sCD163), which further detoxifies and clears residual Hb. We showed that sCD163 and IgG interact with free Hb in the plasma and subsequently the sCD163-Hb-IgG complex is endocytosed into monocytes via FcγR. The endocytosed sCD163 is recycled to restore the homeostasis of CD163 on the monocyte membrane in an autocrine cycle, whereas the internalized Hb is catabolized. Using ex vivo coculture experiments, we demonstrated that the monocyte-derived sCD163 and IgG shuttle residual plasma Hb into the proximal endothelial cells. These findings suggest that CD163 and IgG collaborate to engage monocytes and endothelial cells in a two-pass detoxification mechanism to mount a systemic defense against Hb-induced oxidative stress.

OP001: mRNA expression of S100A8/A9 and rage in FFPE OSCC tissues

Introduction A pro-inflammatory heterodimer S100A8/A9 (calprotectin) of the S100 family of intracellular Ca2+binding proteins is predominantly expressed by myeloid cells and mediates chronic inflammatory diseases. Calprotectin, found to be a potent ligand for RAGE (Receptor for advanced glycation end products), amplifies inflammation by production of reactive oxygen species (ROS). Calprotectin is implicated in causing persistent activation of tumour stromal cells, promoting tumour growth and inducing tumour cell invasion and metastasis. There has been surmounting evidence linking inflammation and cancer. S100A8/A9 expression in oral cancer tissues has not been understood to a large extent. The objective of this study is to assess the levels of calprotectin and RAGE in formalin fixed paraffin embedded (FFPE) oral squamous cell carcinoma (OSCC) tissues. Methodology • FFPE tissues of OSCC, inflamed oral tissue and control: non-inflamed non-neoplastic tissues, n = 10 each, were obtained from our departmental archives. • RNA from the FFPE tissues was isolated using a Qiagen RNAeasy kit and reverse transcribed using mMLV enzyme. cDNA was used as a template for estimation of the gene expression levels using Qualitative Real time PCR technique. Results RNA from the FFPE OSCC samples were successfully isolated. The mRNA levels of calprotectin and RAGE were considerably higher than that of control tissue samples; but were significantly altered in OSCC as compared to the inflamed oral tissues. Conclusion Establishment of an inflammatory microenvironment is key to the progression of inflammation mediated OSCC. Calprotectin has been identified as an important DAMP (endogenous damage-associated molecular pattern) protein which binds to RAGE, a pattern recognition receptor. Inflammatory cytokines and S100A8/A9 seem to have a positive feedback loop in the proliferation of the tumour cells. Our study throws more light on the fact that the dichotomy of S100A8/A9 levels of the OSCC tissues shows that different levels cause the tumours to behave differently.

TLR2 initiates intestinal ischemia/reperfusion induced tissue damage (P4003)

Abstract Reperfusion (the return of blood flow) significantly magnifies ischemia (lack of blood flow) induced tissue damage in multiple clinical conditions including trauma and hemorrhage. During reperfusion, naturally occurring antibodies recognize endogenous damage-associated molecular patterns (DAMP), followed by an excessive complement activation, neutrophil infiltration and inflammatory response which frequently results in an excessive systemic inflammatory response which may lead to death. TLRs recognize DAMP and TLR4 is required for intestinal ischemia-reperfusion (IR). As TLR2 has been proposed to be the receptor for at least one DAMP, the serum protein, β2-glycoprotein I (β2-GPI) which is critical in intestinal ischemia reperfusion (IR), we hypothesized that IR-induced intestinal damage requires TLR2 for subsequent inflammation and tissue damage. Using TLR2-/- mice, we demonstrate that TLR2 is required for excessive IR-induced complement activation and pro-inflammatory cytokine production. TLR2-/- mice not only lacked the appropriate antibody repertoire to induce intestinal IR but treatment with wildtype antibodies was not sufficient to induce tissue damage or inflammation. Compared to wildtype mice, TLR2-/- mice have increased serum β2-GPI but β2-GPI is not deposited on ischemic intestinal tissue. Our data suggest that TLR2 interacts with β2-GPI and is required for neo-antigen expression and initiation of the systemic inflammatory response during intestinal IR.

Toll‐like receptor 2 activation increases adrenergic sensitivity in mesenteric resistance vessels of rats

Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system that recognize microbial pathogens as well as endogenous damage-associated molecular patterns (DAMPS). TLR2 plays a role in cardiovascular diseases (CVD) such as atherosclerosis and heart failure, but its role in vascular function is unknown. We hypothesized that TLR2 activation would increase contractile responses in resistance arteries. We used second order mesenteric arteries from 15-week old Sprague Dawley rats in a small vessel wire myograph. Concentration response curves to norepinephrine (NE; 10−9–10−4 M) were performed in vessels incubated with and without TLR2 agonist Pam3CSK4 [(P3C4); 300ng/mL; 35′ prior incubation], as well as a combination of P3C4 and TLR2 antibody (1 μg/mL; 35′ prior incubation). The sensitivity of the vessels to NE was increased in vessels treated with P3C4 (LogEC50: 6.13± 0.08) compared to control (LogEC50: 5.55± 0.09), and this increase was attenuated by anti-TLR2 (LogEC50: 5.53± 0.05) (p<.05). These results indicate that TLR2 activation increases the sensitivity to adrenergic stimuli in resistance vessels, potentially leading to vascular dysfunction and contributing to CVD such as hypertension.

Inflammatory mechanisms in preeclampsia

Inflammation is a host response triggered by noxious stimuli arising during infection and/or tissue injury, and a controlled inflammatory response is beneficial to fighting infections and healing wounds. Normal pregnancy is characterised by a mild systemic inflammation, however, the inflammation may become detrimental if dysregulated, as seen in preeclampsia. Women with preeclamptic pregnancies have up to eightfold higher risk for cardiovascular diseases later in life, and genetic, clinical and molecular observations support shared underlying inflammatory mechanisms for these diseases. The discoveries that pattern recognition receptors (PRRs) directly sense inflammatory stimuli and activate innate immune cells have greatly increased our molecular understanding of inflammatory diseases. It is hypothesised that some of the clinical manifestations are caused by common underlying inflammatory mechanisms instrumented by PRRs. PRRs activate inflammatory responses by recognising endogenous damage-associated molecular patterns (DAMPs) released from injured tissues and stressed or dying cells; including degraded extracellular matrix components, heat-shock proteins, HMGB1 proteins, nucleic acids and crystalline structures such as cholesterol crystals. In preeclampsia, many such DAMPs are known to contribute to both the local placental inflammation and to systemic inflammation and endothelial dysfunction, but with largely unknown molecular action. Defining the role of PRRs in preeclampsia by learning from similar mechanisms associated with cardiovascular diseases will help us in improved understanding of this complex inflammatory syndrome.

The crucial role of the MyD88 adaptor protein in the inflammatory response induced by Bothrops atrox venom

Most snake accidents in North Brazil are attributed to Bothrops atrox, a snake species of the Viperidae family whose venom simultaneously induces local and systemic effects in the victims. The former are clinically more important than the latter, as they cause severe tissue lesions associated with strong inflammatory responses. Although several studies have shown that inflammatory mediators are produced in response to B. atrox venom (BaV), there is little information concerning the molecular pathways involved in innate immune system signaling. Myeloid differentiation factor 88 (MyD88) is an adaptor molecule responsible for transmitting intracellular signals from most toll-like receptors (TLRs) after they interact with pathogen-associated molecular patterns (PAMPs) or other stimuli such as endogenous damage-associated molecular patterns (DAMPs). The MyD88-dependent pathway leads to activation of transcription factors, which in turn induce synthesis of inflammatory mediators such as eicosanoids, cytokines and chemokines. The aim of this study was to investigate the involvement of MyD88 on the acute inflammatory response induced by BaV. Wild-type (WT) C57BL/6 mice and MyD88 knockout (MyD88−/−) mice were intraperitoneally injected with BaV. Compared to WT mice, MyD88−/− animals showed an impaired inflammatory response to BaV, with lower influx of polymorphonuclear and mononuclear cells to the peritoneal cavity. Furthermore, peritoneal leukocytes from BaV-injected MyD88−/− mice did not induce COX-2 or LTB4 protein expression and released low concentrations of PGE2. These mice also failed to produce Th1 and Th17 cytokines and CCL-2, but IL-10 levels were similar to those of BaV-injected WT mice. Our results indicate that MyD88 signaling is required for activation of the inflammatory response elicited by BaV, raising the possibility of developing new therapeutic targets to treat Bothrops sp. poisoning.

Can microRNAs keep inflammasomes in check?

Inflammasomes are multi-protein signaling platforms that are primed upon sensing pathogen-associated molecular patterns (PAMPs) as well as endogenous damage-associated molecular patterns (Kolliputi et al., 2010, 2012). Once primed, a complex forms between the inflammasome sensor, an adaptor protein with a caspase recruiter domain (ASC), and caspase-1, which leads to the cleavage of pro-inflammatory cytokines Interleukin-1beta and Interleukin-18 (IL-1B, IL-18). A specific inflammasome sensor, nucleoside-triphosphatase domain (NACHT), leucine rich repeat (LRR), and pyrin domain (PYD) domains-containing protein 3 (NLRP3) has garnered the attention of many secondary to its ability to function as a general sensor of cell stress, possessing a large number of endogenous and exogenous activators compared to other inflammasome sensors such as Interferon-inducible protein (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4). This pathway has also been implicated in numerous diseases like gout, alzheimers, obesity, and diabetes (Heneka et al., 2013; Wei et al., 2013). Given the prevalent evidence that this pathway is involved in many medical conditions, current and further studies about inflammasome regulation could potentially allow pharmaceutical researchers to develop drugs for currently incurable diseases. The NLRP3 inflammasome complex can be regulated in three main ways; the degree of which the inflammasome complex is expressed, the amount of NLRP3 activators present and post-transcriptional modulation via microRNAs (miRNA). miRNAs are defined as a class of non-coding oligonucleotides which function in post-transcriptional regulation of gene expression (Bartel, 2009; Tamarapu et al., 2012). A particular miRNA may have multiple targets, and a given mRNA may have several miRNAs that may exhibit regulatory function on itself (Krek et al., 2005; Jalali et al., 2012). These oligonucleotide sequences have become a hot area of research as they are proving to become relevant in the pathogenesis and possible cure to multiple medical conditions (Holohan et al., 2012). In atherosclerosis it has been shown that elevated miR-155 levels are found in pro-inflammatory macrophages as well as in atherosclerotic lesions (Wei et al., 2013). In the September 2012 edition of the Journal of Immunology, Bauernfeind et al. (2012) present exciting findings on inflammasome sensor, NLRP3, by showing its negative regulation via a type of miRNA, miR-223. To investigate the potential role of post-transcriptional regulation on the inflammasome pathway, Bauernfeind et al. (2012) conducted several experiments in different cell lineages. Their initial study involved examining luciferase activity after transfection with a plasmid armed with luciferase on the 3′UTR of human NLRP3, as well as a genome wide miRNA precursor library in 293T cells. Of the miRNA precursor library, miR-223 showed the greatest promise, decreasing the activity of NLRP3. Bauernfeind et al. (2012) showed that miR-223 levels increase during granulopoiesis and are highest in mature neutrophils, while expression is absent in T and B cells. They also noted an inverse relationship with regards to miR-223 and NLRP3 during the maturation process in the monocyte lineage, showing a decrease in miR-223 levels, an increase in NLRP3 transcripts, and caspase activation after culturing with granulocyte-macrophage colony-stimulating factor (GM-CSF). This was also proven by Haneklaus et al. (2012) as they showed low NLRP3 protein levels in monocytes and significantly higher levels in macrophages, indicating that the threshold for inflammasome activation is variable throughout granulopoiesis and different cell lines. The work of Bauernfeind et al. (2012) has shed light on a key mechanism in the inflammatory cascade, a process implicated in numerous diseases. Finding endogenous and exogenous mediators that can control the unchecked inflammation seen in these conditions is an important step to discover pharmaceutical intervention and even possible cures. Hopefully these studies will set the foundation for the exploration of the regulatory effects of miR-223 and other miRNAs in regulating inflammation in numerous medical conditions in the near future.

Epstein-Barr virus-driven lymphomagenesis in the context of human immunodeficiency virus type 1 infection

Epstein–Barr virus (EBV) is a ubiquitous human γ-herpes virus which establishes a life-long asymptomatic infection in immunocompetent hosts. In human immunodeficiency virus type 1 (HIV-1) infected patients, the impaired immunosurveillance against EBV may favor the development of EBV-related diseases, ranging from lymphoproliferative disorders to B cell non-Hodgkin’s lymphomas (NHL). Antiretroviral therapy (ART) has significantly modified the natural course of HIV-1 infection, resulting in decreased HIV-1 plasmaviremia, increased CD4 lymphocytes, and decreased opportunistic infections, indicating a restoration of immune functions. However, the impact of ART appears to be less favorable on EBV-related malignancies than on other AIDS-defining tumors, such as Kaposi’s sarcoma, and NHL remains the most common cancer during the ART era. EBV-driven tumors are associated with selective expression of latent oncogenic proteins, but uncontrolled lytic cycle with virus replication and/or reactivation may favor cell transformation, at least in the early phases. Several host’s factors may promote EBV reactivation and replication; besides immunodepression, inflammation/chronic immune stimulation may play an important role. Microbial pathogen-associated molecular patterns and endogenous damage-associated molecular patterns, through Toll-like receptors, activate the immune system and may promote EBV reactivation and/or polyclonal expansion of EBV-infected cells. A body of evidence suggests that chronic immune stimulation is a hallmark of HIV-1 pathogenesis and may persist even in ART-treated patients. This review focuses on lymphomagenesis driven by EBV both in the context of the natural history of HIV-1 infection and in ART-treated patients. Understanding the mechanisms involved in the expansion of EBV-infected cells is a premise for the identification of prognostic markers of EBV-associated malignancies.

DAMPs, PAMPs, and the Origins of SIRS in Bacterial Sepsis

DAMPs, PAMPs, and the Origins of SIRS in Bacterial Sepsis

TLR2 and TLR4 in the Brain Injury Caused by Cerebral Ischemia and Reperfusion

Brain injury caused by cerebral ischemia/reperfusion is a complicated pathophysiological course, in which inflammation is thought to play an important role. Toll-like receptors are a type of transmembrane proteins, which can recognize either exogenous pathogen-associated molecular patterns or endogenous stress or damage-associated molecular patterns in the innate immune system and initiate inflammatory responses. Among Toll-like receptors, TLR2 and TLR4 are found to be more important than others in the pathological progression of cerebral injury due to ischemia and reperfusion. This review will focus on the biological characteristics and functions of TLR2 and TLR4 and their downstream signal pathways.

“Adapting to terminologies involved in host immune response”

The innate immunity can sense the exogenous pathogen motifs referred to as pathogen associated molecular patterns(PAMPs), as well as other signals associated with infection, such as host components like endogenous products released from dying or damaged cells were called damage associated molecular patterns(DAMPs). Thus the immune response is induced not only by exogenous microbial infection, but also by endogenous sterile tissue damage and degeneration. Based on the common recognition system and the similar inflammatory response, some authors use the term “alarmins” to categorize endogenous DAMPs as separate from pathogen-derived molecules. In this review the authors attempt to familiarize the periodontal community with the terminologies involved in host immune response.